Cyclic ureas useful as antiarrhythmic and antifibrillatory agents

The cyclic ureas, and the pharmaceutically-acceptable salts and esters thereof, of the present invention are useful as antiarrhythmic and antifibrillatory agents and have the following general structure: ##STR1## wherein X, Y, A, L, R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are defined as in the Specification.

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Claims

1. A cyclic urea compound which has the structure: ##STR12## wherein a) X is a saturated or unsaturated, substituted or unsubstituted 6-membered carbocycle;

b) R is a covalent bond;
c) Y is a saturated or unsaturated, substituted or unsubstituted 5-membered heterocycle, wherein said heterocycle has one or two heteroatoms selected from O, S or N;
d) R.sub.1, R.sub.2, and R.sub.3 are substituents on the X moiety and are independently selected from the group consisting of H, Cl, F, Br, NH.sub.2, CF.sub.3, OH, SO.sub.3 H, CH.sub.3, SO.sub.2, NH, COOH, alkoxy, alkoxycarbonyl, alkyl, hydroxyalkyl, carboxyalkyl, amino alkyl, acylamino, and acyloxy;
e) L is a linking moiety and is selected from the group consisting of alkylamino, alkenylamino, alkylimino, alkenylimino, and acylamino, wherein the carbon-containing end of L is bound, through R, at X; and wherein the nitrogen atom of L is bound to the nitrogen atom at the 3-position of the cyclic urethane ring moiety;
f) R.sub.4 is selected from the group consisting of alkyl, alkenyl, alkynyl, alkylacyl, and heteroalkyl;
g) A is a substituted or unsubstituted; saturated or unsaturated, straight-chain or branched C.sub.1 -C.sub.8 heteroalkyl; or a substituted or unsubstituted, saturated or unsaturated, heterocycle having 5-, 6- or 7-members and one or two heteroatoms selected from O, N or S; and heteroalkyl A and heterocycle A have at least one nitrogen atom, which nitrogen atom is adjacent to R.sub.4; and
h) R.sub.5 is a substituted or unsubstituted C.sub.1 alkyl;

2. A cyclic urea compound according to claim 1 having the structure: ##STR13## wherein a) X is a saturated or unsaturated, substituted or unsubstituted phenyl;

b) R is a covalent bond;
c) Y is a furanyl;
d) R.sub.1, R.sub.2, and R.sub.3 are substituents on the X moiety and are independently selected from the group consisting of H, Cl, F, Br, NH.sub.2, CF.sub.3, OH, SO.sub.3 H, CH.sub.3, SO.sub.2, NH, COOH, alkoxy, alkoxycarbonyl, alkyl, hydroxyalkyl, carboxyalkyl, amino alkyl, acylamino, and acyloxy;
e) L is a linking moiety and is selected from the group consisting of alkylamino, alkenylamino, alkylimino, alkenylimino, and acylamino, wherein the carbon-containing end of L is bound, through R, at X; and wherein the nitrogen atom of L is bound to the nitrogen atom at the 3-position of the cyclic urethane ring moiety;
f) R.sub.4 is selected from the group consisting of alkyl, alkenyl, alkynyl, alkylacyl, and heteroalkyl;
g) A is a substituted or unsubstituted; saturated or unsaturated, straight-chain or branched C.sub.1 -C.sub.8 heteroalkyl; or a substituted or unsubstituted, saturated or unsaturated, heterocycle having 5-, 6- or 7-members and one or two heteroatoms selected from O, N or S; and heteroalkyl A and heterocycle A have at least one nitrogen atom, which nitrogen atom is adjacent to R.sub.4; and
h) R.sub.5 is a substituted or unsubstituted C.sub.1 alkyl;

3. A cyclic urea compound having the following structure: ##STR14## wherein a) X is phenyl, pyridinyl, thienyl, pyrimidinyl, furanyl, cyclohexyl, oxazolyl, naphthyl, and quinolinyl;

b) R is nil or a covalent bond;
c) Y is phenyl, pyridinyl, thienyl, pyrimidinyl, furanyl, cyclohexyl, oxazolyl, naphthyl, and quinolinyl;
d) R.sub.1, R.sub.2, and R.sub.3 are substituents on the X moiety and are independently selected from the group consisting of H, Cl, F, Br, NH.sub.2, CF.sub.3, OH, SO.sub.3 H, CH.sub.3, SO.sub.2, NH, COOH, alkoxy, alkoxycarbonyl, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, acylamino, and acyloxy;
e) L is a linking moiety and is selected from the group consisting of alkylamino, alkenylamino, alkenylimino, alkylimino, and acylamino, wherein the nitrogen atom thereof is bound to the nitrogen atom at the 1-position of the cyclic urea ring moiety;
f) R.sub.4 is selected from the group consisting of alkyl, alkenyl, alkynyl, alkyl, alkylacyl, and heteroalkyl;
g) A is a substituted or unsubstituted; saturated or unsaturated, straight-chain or branched C.sub.1 -C.sub.8 heteroalkyl; or a substituted or unsubstituted, saturated or unsaturated, heterocycle having 6- or 7-members and one or two heteroatoms selected from N or S; and may not have an oxygen atom; and heteroalkyl A and heterocycle A has at least one nitrogen atom, and said nitrogen atom is adjacent to R.sub.4; and
h) R.sub.5 is a substituted or unsubstituted C.sub.1 alkyl; and the pharmaceutically-acceptable salts and esters thereof.

6. A cyclic urea compound having the following structure: ##STR17## wherein a) wherein the "X-R-Y" portion of the structure is selected from one of the following: ##STR18## b) wherein R.sub.1, R.sub.2, and R.sub.3 are independently selected from the group consisting of H, Cl, F, Br, NH.sub.2, CF.sub.3, OH, SO.sub.3 H, CH.sub.3 SO.sub.2 NH, COOH, alkoxy, alkoxycarbonyl, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, acyloxy, and acylamino;

c) L is a linking moiety and is selected from the group consisting alkylamino, alkenylamino, alkenylimino, alkylimino, and acylamino; wherein the nitrogen atom thereof is bound to the nitrogen atom at the 1-position of the cyclic urea ring moiety;
d) wherein R.sub.4 is selected from the group consisting of alkenyl, alkynyl, alkylacyl, and heteroalkyl;
e) R.sub.5 is a substituted or unsubstituted C.sub.1 alkyl; and
f) wherein the A portion of the structure is selected from one of the following: ##STR19## and the pharmaceutically-acceptable salts and esters thereof.

7. A cyclic urea compound having the following structure: ##STR20## a) wherein the "X-R-Y" portion of the structure is selected from one of the following: ##STR21## b) wherein R.sub.1, R.sub.2, and R.sub.3 are independently selected from the group consisting of H, Cl, F, Br, NH.sub.2, CF.sub.3, OH, SO.sub.3 H, CH.sub.3 SO.sub.2 NH, COOH, alkoxy, alkoxycarbonyl, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, acyloxy, and acylamino;

c) wherein R.sub.4 is selected from the group consisting of alkenyl, alkynyl, alkylacyl, and heteroalkyl;
d) R.sub.5 is a substituted or unsubstituted C.sub.1 alkyl; and
e) wherein the A portion of the structure is selected from one of the following: ##STR22## and the pharmaceutically-acceptable salts and esters thereof.

8. A cyclic urea compound having the general structure: ##STR23## wherein a) R.sub.1, R.sub.2, and R.sub.3 are independently selected from the group consisting of H, Cl, F, Br, NH.sub.2, CF.sub.3, OH, SO.sub.3 H, CH.sub.3 SO.sub.2 NH, COOH, alkoxy, alkoxycarbonyl, alkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, acyloxy and acylamino;

b) R.sub.4 is selected from a group consisting of an alkyl, alkenyl, alkynyl, alkylacyl, and heteroalkyl;
c) A is a substituted or unsubstituted, saturated or unsaturated, straight-chain or branched C.sub.1 -C.sub.8 heteroalkyl or a substituted or unsubstituted, saturated or unsaturated heterocycle having 5-, 6-, or 7-members; wherein said heterocycle has one or more heteroatoms selected from nitrogen, sulfur, or oxygen; and
d) R.sub.5 is a substituted or unsubstituted C.sub.1 alkyl;

10. A cyclic urea compound having the following structure: ##STR25## (a) wherein the "X-R-Y" portion of the structure is selected from one of the following: ##STR26## (b) L is a linking moiety and is selected from the group consisting of alkylamino, alkenylamino, alkenylimino, alkylimino, and acylamino; wherein the nitrogen atom thereof is bound to the nitrogen atom at the 1-position of the cyclic urea ring moiety;

(c) wherein R.sub.4 is selected from the group consisting of alkenyl, alkynyl, alkylacyl, and heteroalkyl;
(d) wherein the A portion of the structure is selected from one of the following: ##STR27## and the pharmaceutically acceptable salts and esters thereof.

11. A compound according to claim 1 wherein X is unsubstituted and R.sub.1, R.sub.2, and R.sub.3 are hydrogen.

12. A compound according to claim 11 wherein R.sub.1, R.sub.2, and R.sub.3 are independently selected from the group consisting of hydrogen, Cl, F, Br, CH.sub.3, and OH.

13. A compound according claim 1 wherein Y is a 5-membered heterocycle.

14. A compound according to claim 1 wherein R is adjacent to X at the 1-position of X, and to Y at the 5-position of Y.

15. A compound according to claim 14 wherein Y is connected to the carbon-containing end of L at the 2-position of Y.

16. A compound according to claim 13 wherein a heteroatom of Y is oxygen at the 1-position of said heterocycle.

17. A compound according to claim 16 wherein one of R.sub.1, R.sub.2, or R.sub.3 is Cl, F, or Br and two of R.sub.1, R.sub.2 or R.sub.3 are H.

19. A compound according to claim 1 wherein X is substituted with two or more substituents selected from the group consisting of Cl, OH, methoxy, methyl, and benzoyl.

20. A compound according to claim 1 wherein L is selected from the group consisting of alkylimino, alkylamino, and alkenylimino.

21. A compound according to claim 1 wherein R.sub.4 is a C.sub.3 -C.sub.6 alkyl.

22. A compound according to claim 1 wherein R.sub.4 is a substituted alkyl.

23. A compound according to claim 1 wherein A is a heteroalkyl.

24. A pharmaceutical composition is comprised of a safe and effective amount of from 15 to 90% of a cyclic urea compound of claim 1, or mixtures thereof, and from 10 to 85% pharmaceutically-acceptable excipients.

25. A pharmaceutical composition according to claim 24, wherein the pharmaceutically-acceptable excipients are selected from the group consisting of polymers, resins, plasticizers, fillers, binders, lubricants, glidants, disintegrants, solvents, co-solvents, buffer systems, surfactants, preservatives, sweetening agents, flavoring agents, pharmaceutical grade dyes or pigments, and viscosity agents.

26. A pharmaceutical composition according to claim 6 comprised of from 15-95% of the cyclic urea active ingredient; 0-2% flavoring agents; 0-50% co-solvents; 0-5% buffer system; 0-2% surfactants; 0-2% preservatives; 0-5% sweeteners; 0-5% viscosity agents; 0-75% fillers; 0.5-2% lubricants; 1-5% glidants; 4-15% disintegrants; and 1-10% binders.

27. A method of treatment for humans or other mammals afflicted with cardiac arrhythmias and/or cardiac fibrillation comprised of administering to said human or other mammal a safe and effective amount of the pharmaceutical composition of claim 6.

28. A pharmaceutical composition for the treatment of cardiac arrhythmia or cardiac fibrillation comprised of from 15 to 90% of a cyclic urea compound of claim 1, or any mixtures thereof, and from 10 to 85% pharmaceutically-acceptable excipients.

29. A pharmaceutical composition for the treatment of cardiac arrhythmia or cardiac fibrillation comprised of from 15 to 90% of a cyclic urea compound of claim 2, or any mixtures thereof, and from 10 to 85% pharmaceutically-acceptable excipients.

30. A pharmaceutical composition for the treatment of cardiac arrhythmia or cardiac fibrillation comprised of from 15 to 90% of a cyclic urea compound of claim 3, or any mixtures thereof, and from 10 to 85% pharmaceutically-acceptable excipients.

31. A pharmaceutical composition for the treatment of cardiac arrhythmia or cardiac fibrillation comprised of from 15 to 90% of a cyclic urea compound of claim 4 or any mixtures thereof, and from 10 to 85% pharmaceutically-acceptable excipients.

32. A pharmaceutical composition for the treatment of cardiac arrhythmia or cardiac fibrillation comprised of from 15 to 90% of a cyclic urea compound of claim 5, or any mixtures thereof, and from 10 to 85% pharmaceutically-acceptable excipients.

33. A pharmaceutical composition for the treatment of cardiac arrhythmia or cardiac fibrillation comprised of from 15 to 90% of a cyclic urea compound of claim 6, or any mixtures thereof, and from 10 to 85% pharmaceutically-acceptable excipients.

34. A pharmaceutical composition for the treatment of cardiac arrhythmia or cardiac fibrillation comprised of from 15 to 90% of a cyclic urea compound of claim 7, or any mixtures thereof, and from 10 to 85% pharmaceutically-acceptable excipients.

35. A method of treatment for humans or other mammals afflicted with cardiac arrhythmias and/or cardiac fibrillation comprised of administering to said human or other mammal a pharmaceutical composition comprising from 15 to 90% of a cyclic urea compound according to claim 18, pharmaceutically-acceptable salt and esters thereof, or mixtures thereof.

36. A method of treatment for humans or other mammals afflicted with cardiac arrhythmias and/or cardiac fibrillation comprised of administering to said human or other mammal a pharmaceutical composition comprising from 15 to 90% of a cyclic urea compound according to claim 9, pharmaceutically-acceptable salt and esters thereof, or mixtures thereof.

37. A method of treatment for humans or other mammals afflicted with cardiac arrhythmias and/or cardiac fibrillation comprised of administering to said human or other mammal a pharmaceutical composition comprising from 15 to 90% of a cyclic urea compound according to claim 10, pharmaceutically-acceptable salt and esters thereof, or mixtures thereof.

Referenced Cited
U.S. Patent Documents
3254075 May 1966 Ebetino
3415821 December 1968 Davis et al.
3992374 November 16, 1976 Rufer et al.
4393204 July 12, 1983 Pelosi, Jr.
4543359 September 24, 1985 Ellis et al.
4689341 August 25, 1987 Diamond et al.
4705799 November 10, 1987 Gregory
4707499 November 17, 1987 Baran et al.
4713832 December 15, 1987 Pascal
4720580 January 19, 1988 Buzby et al.
4775670 October 4, 1988 Sykes et al.
4870095 September 26, 1989 Bailey
4876262 October 24, 1989 Oinuma et al.
4963561 October 16, 1990 Lesher et al.
4966967 October 30, 1990 Lumma, Jr. et al.
Foreign Patent Documents
0235752 September 1987 EPX
0347733 December 1989 EPX
0431945 December 1991 EPX
8705297 September 1987 WOX
Other references
  • Bigger, J. T. and Hoffman, B. F., "Antiarrhythmic Drugs", Ch. 35 in Goodman and Gilman's The Basis of Pharmaceutical Therapeutics, 8th ed., ed., A. G. Gilman, pp. 840-873. Bigger, J. T., "Antiarrhythmic Treatment: An Overview", American Journal of Cardiology, vol. 53, pp. 8B-16B, Feb. 27, 1984. Woosley, R. L., "Antiarrhythmic Agents", in The Heart, Ch. 95, pp. 1682-1711, ed. J. W. Hurst, New York, McGraw-Hill (1990). Woosley, R. L., "Antiarrhythmic Drugs", Annual Review. Pharmacology and Toxicology, vol. 31, pp. 427-455 (1991). Morganroth, J. and Biggger, J. T., "Pharmacological Managment of Ventricular Arrhythmias After the Cardiac Arrhythmia Suppression Trial", American Journal of Cardiology, vol. 65, pp. 1497-1503 (1990). Goldstein, S., "Toward a New Understanding of the Mechanism and Prevention of Sudden Death in Coronary Heart Disease", Circulation, vol. 82(1):pp. 284-288 (1990). Echt, D. S. et al. "Mortality and Morbidity in Patients Receiving Encainide, Flecainide, or Placebo: The Cardiac Arrhythmia Suppression Trial", New England Journal of Medicine, vol. 324, pp. 781-788 (1991). Coplen, S. E. et al. "Efficacy and Safety of Quinidine Therapy for Maintenance of Sinus Rhythm After Cardioversion: A Meta-analysis" Circulation, vol. 82, pp. 1106-1116 (1990).
Patent History
Patent number: 5691369
Type: Grant
Filed: Jun 7, 1995
Date of Patent: Nov 25, 1997
Assignee: The Proctor & Gamble Company (Cincinnati, OH)
Inventors: Stanford Salvatore Pelosi, Jr. (Norwich, NY), Chia-Nien Yu (Norwich, NY)
Primary Examiner: Yogendra N. Gupta
Attorneys: Karen F. Clark, David L. Suter, Jacobus C. Rasser
Application Number: 8/479,256